Recent studies with transmitochondrial cybrids revealed that the presence of cancer cellderived mitochondria could alter the behavior of the host cell. In order to understand the genetic basis of this phenomenon, we examined host cell gene profile in transmitochondrial cybrids with mitochondria derived from breast cancer cells. Preliminary results indicated distinct differences in nuclear gene expression between cybrids with normal mitochondria and cybrids with cancer cellderived mitochrondria.. We also observed marked differences in nuclear gene expression patterns between cybrids harboring different cancer cellderived mitochrondria that behave differently with respect to tumorigenicity and various key regulators in energy metabolism. Importantly, the gene signatures of these cybrids mimic the breast cancer profile. To reveal the potential transcriptional regulators of this gene set, promoter analysis was performed. Of the 12 known genes validated by real-time PCR, 5 genes (42%) demonstrated the presence of TP53 binding site, while NF-kappaB binding sites were present in 6 genes (50%). Four genes contain sites for both factors. The potential regulation by p53 or NF-KappaB was also confirmed through reconstruction of gene networks by systems biological analysis. These results suggested that mitochondria derived from breast cancer cell lines could communicate and effect transcription activities of the nucleus. Thus, genetically altered mitochondria may actively participate in breast cancer development.